Resveratrol mediates the miR-149/HMGB1 axis and regulates the ferroptosis pathway to protect myocardium in endotoxemia mice

Endotoxemia is a common complication often used to model the acute inflammatory response associated with endotoxemia. Resveratrol has been shown to exert a wide range of therapeutic effects due to its anti-inflammatory and antioxidant properties. This study explored the effect of resveratrol on endotoxemia. Lipopolysaccharide (LPS)-induced endotoxemia mouse model and endotoxemia myocardial injury cell model were established and treated with resveratrol. Cardiomyocyte activity, lactate dehydrogenase (LDH) content in cell supernatant, glutathione (GSH) consumption, lipid reactive oxygen species (ROS) production, and iron accumulation were detected. Cardiac function indexes [left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), ejection fraction (EF)%, and fractional shortening (FS)%] were measured using echocardiography. The creatine kinase muscle/brain isoenzyme (CK-MB) and CK levels in the serum were detected using an automatic biochemical analyzer. The downstream target of miR-149 was predicted, and the binding relationship between miR-149 and high mobility group box 1 (HMGB1) was verified using a dual-luciferase assay. miR-149 and HMGB1 expressions were detected using RT-qPCR and Western blot. After resveratrol treatment, cardiomyocyte viability and GSH were increased, and LDH secretion, lipid ROS production, lipid peroxidation, and iron accumulation were decreased, and cardiac function and cardiomyocyte injury were improved. Resveratrol improved LPS-induced endotoxemia cardiomyocyte injury by upregulating miR-149 and inhibiting ferroptosis. Resveratrol inhibited HMGB1 expression by upregulating miR-149. HMGB1 upregulation reversed the inhibitory effect of miR-149 on LPS-induced ferroptosis in cardiomyocytes. Resveratrol upregulated miR-149 and downregulated HMGB1 to inhibit ferroptosis and improve myocardial injury in mice with LPS-induced endotoxemia. Collectively, resveratrol upregulated miR-149, downregulated HMGB1, and inhibited the ferroptosis pathway, thus improving cardiomyocyte injury in LPS-induced endotoxemia.NEW & NOTEWORTHY Sepsis is an unusual systemic reaction. Resveratrol is involved in sepsis treatment. This study explored the mechanism of resveratrol in sepsis by regulating the miR-149/HMGB1 axis.